CROSS BRIDGE KINETICS AND REGULATION

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Vascular smooth muscle is an essential regulator of the distribution of blood flow and its abnormalities contribute to high blood pressure, atherosclerosis, coronary restenosis and shock. Other smooth muscles play similarly important roles and regulate airway function and gastrointestinal, uterine and bladder movements. This project will determine the regulations and kinetics of crossbridge cycling, the fundamental mechanism of contraction of all smooth muscles, determines the kinetics of crossbridge cycling, and its structural basis is the variable, smooth muscle-specific expression of essential light chain and heavy chain myosin isoforms. Functional studies will be conducted on smooth muscles containing, respectively, myosins with or without the heavy chain insert and selectively modified by targeted expression or exchange of light chain isoforms. The off-rates of ADP and inorganic phosphate from crossbridges will be determined with novel fluorescent probes developed by The Core, and will be related to the rates of force development and shortening velocity. We will identify the kinases, phosphates and other proteins involved in fine-tuning the balance between myosin light chain kinase and phosphatase activities (collaboration with T. Haystead) and determine the physiological role of the phosphatase- regulating protein, telokin, through functional studies of mouse models deficient (knockout) or subjected to targeted over-expression of this protein (collaboration with G. Owens).